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Trial registered on ANZCTR


Registration number
ACTRN12619001428156
Ethics application status
Approved
Date submitted
18/09/2019
Date registered
15/10/2019
Date last updated
12/05/2022
Date data sharing statement initially provided
15/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Effects of Infraslow Neurofeedback in Anxiety and Depression (the ISAD study)
Scientific title
The ISAD (InfraSlow neurofeedback for Anxiety and Depression): a trans-diagnostic, randomized, double-blind, sham-controlled, dose-response, parallel-group trial
Secondary ID [1] 299332 0
None
Universal Trial Number (UTN)
U1111-1239-1222
Trial acronym
ISAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anxiety 314476 0
Depression 314477 0
Internalising Disorders 324141 0
Condition category
Condition code
Mental Health 312810 312810 0 0
Anxiety
Mental Health 312811 312811 0 0
Depression
Mental Health 321615 321615 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Infraslow neurofeedback (IS-NFB) is a non-invasive technique that uses real time recordings of brain activity to teach self-regulation of brain function via operant conditioning by generating a sound when the brain exhibits the targeted infraslow (<0.1 Hz) brain activity. Infra-slow neurofeedback is carried out with participants sitting upright in a comfortable chair. The first step is to apply the 19-electrode cap on the scalp. The electrodes on the cap, which are like little cup-shaped discs, are kept in place with a special conducting jelly put on them before attached to the scalp. The electrode cap will be connected to an amplifier and a computer which allow the recording of infraslow brain activity. Participants will be asked to close their eyes, relax and listen to the sound being played.

4 parallel arms:
arm 1: 12 sessions of real IS-NFB modulating default mode network (DMN) activity (n=15 women)
arm 2: 12 sessions of real IS-NFB modulating DMN & salience network (SN) connectivity (n=15 women)
arm 3: 6 sessions of sham IS-NFB followed by 6 sessions of real IS-NFB modulating DMN activity (n=15 women)
arm 4: 6 sessions of sham IS-NFB followed by 6 sessions of real IS-NFB modulating DMN & SN connectivity (n=15 women).

IS-NFB will be performed individually on participants by a trained researcher with experience delivering IS-NFB treatment. Sessions will last 30 minutes and take place 3 times per week over 4 weeks. All interventions will take place in a clinic room at the University of Otago (Dunedin Hospital).
Intervention code [1] 315601 0
Treatment: Devices
Comparator / control treatment
arm 3: 6 sessions of sham IS-NFB followed by 6 sessions of real IS-NFB modulating DMN activity (n=15 women)

arm 4: 6 sessions of sham IS-NFB followed by 6 sessions of real IS-NFB modulating DMN & SN connectivity (n=15 women).

The control is a combination of placebo/sham and dose comparison. It is placebo/sham because outcomes will be compared after 6 sessions of real IS-NFB (arms 1 & 2) and 6 sessions of sham IS-NFB (arms 3 & 4). It is dose comparison because outcomes will also be compared after 12 sessions of real IS-NFB (arms 1 & 2) and 6 sessions of real IS-NFB (arms 3 & 4).

For sham IS-NFB, a random selection of pre-recorded 30-min IS-NFB sessions will be played. For ethical reasons, we chose not to provide a 12 session sham IS-NFB group and instead implement a staggered/delayed start design thereby assuring all participants received real IS-NFB based on the assumption that participants would benefit only from the real IS-NFB.
Control group
Placebo

Outcomes
Primary outcome [1] 321433 0
Hospital Anxiety and Depression Scale (HADS)
Timepoint [1] 321433 0
Immediately following 6th IS-NFB session, 12th IS-NFB session, and 1 month post IS-NFB
Secondary outcome [1] 374927 0
Whole-brain activity (high density EEG)
Timepoint [1] 374927 0
Immediately following 6th IS-NFB session, 12th IS-NFB session, and 1 month post IS-NFB
Secondary outcome [2] 374928 0
Heart rate variability (HRV).

Heart rate (HR) will be monitored via photoplethysmography using a portable, one channel, real-time data acquisition device attached to the finger or earlobe. HR will be assessed during both spontaneous (6 min) and paced (6 min; 12 breaths per minute) breathing.
Timepoint [2] 374928 0
Immediately following 6th IS-NFB session, 12th IS-NFB session, and 1 month post IS-NFB
Secondary outcome [3] 374930 0
Intolerance of Uncertainty Scale (IUS-12)
Timepoint [3] 374930 0
Immediately following 6th IS-NFB session, 12th IS-NFB session, and 1 month post IS-NFB
Secondary outcome [4] 375636 0
Whole-brain connectivity (high density EEG)
Timepoint [4] 375636 0
Immediately following 6th IS-NFB session, 12th IS-NFB session, and 1 month post IS-NFB
Secondary outcome [5] 377306 0
Repetitive Thinking Questionnaire (RTQ-10)
Timepoint [5] 377306 0
Immediately following 6th IS-NFB session, 12th IS-NFB session, and 1 month post IS-NFB
Secondary outcome [6] 402389 0
43-item Discontinuation-Emergent Signs and Symptoms Inventory (DESS)
Timepoint [6] 402389 0
Immediately prior each IS-NFB session & 1 month post IS-NFB
Secondary outcome [7] 409576 0
Inventory of Depression and Anxiety Symptoms – 2nd Version (IDAS-II)'
Timepoint [7] 409576 0
Immediately following 6th IS-NFB session, 12th IS-NFB session, and 1 month post IS-NFB
Secondary outcome [8] 409577 0
Multidimensional Emotional Disorder Inventory (MEDI)
Timepoint [8] 409577 0
Immediately following 6th IS-NFB session, 12th IS-NFB session, and 1 month post IS-NFB

Eligibility
Key inclusion criteria
1. Women aged 18-64 years with (re)current anxiety and/or depression (i.e. GAD, SOC, MDD)
2. No or stable use of medications for at least 4 weeks with no intention to change.
Minimum age
18 Years
Maximum age
64 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Taking new medications (less than 4 weeks), short-acting benzodiazepines or other drugs that may influence autonomic activity (e.g. amphetamines)
2. Current externalising disorder (alcohol/substance use disorder, antisocial personality disorder, suicidality)
3. Current thought disorder (mania/bipolar disorder, psychoses)
4. Current pregnancy
5. Pacemaker
6. Tinnitus

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Yes. A researcher from the group who has no direct contact with the participants will conduct the randomisation process
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
To ensure balanced sample size across the sham and IS-NFB groups over time, block randomisation will be performed. A researcher from the group who has no direct contact with the participants will conduct the randomisation process using the program on randomization.com. This tool is a valid randomisation program utilised by clinical trial researchers.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
We intiially intended to use ‘authorised deception’ in order to prevent negative expectations or deficits in motivation with respect to sham IS-NFB. Clinical participants were to be alerted to the possible presence of deception in the PIS/CF, grant its implementation with their signed informed consent., and fully debriefed at the end of the study. We, however, subsequently chose to remove the 'authorised deception' prior to enrolment commencement.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
To date, this is the first RCT examining the effect of IS-NFB on individuals with anxiety and depression, thus this is a convenience sample as no formal power calculations can be made. Our research group’s previous IS-NFB pilot study found significant differences in brain activity and self-reported measures in food addicted women after 6 sessions of real IS-NFB(n=11) relative to sham (n=10).

Primary outcomes: Alterations in self-reported symptomatology following IS-NFB will be investigated and quantified from the aforementioned battery of tests. These dependent variables will then be statistically compared using mixed 2-way repeated measures ANOVA. The direction and the magnitude of change in the dependent variables will inform the underpinning change in symptomatology and whether it is clinically meaningful.

Secondary outcomes: eLORETA will be used to perform a voxel-by-voxel analysis (comprising 6239 voxels) for the different frequency bands of the current density distribution to identify potential differences in brain electrical activity at baseline, 6 sessions, 12 sessions and during 1 month follow-up. Nonparametric statistical analyses of functional eLORETA images (statistical nonparametric mapping: SnPM) will be performed for each contrast using eLORETA’s built-in voxel wise randomization tests (5000 permutations) and employing a log-F-ratio statistic for independent groups with a threshold P < 0.05. As explained by Nichols and Holmes, the statistical nonparametric mapping method does not rely on an assumption of a Gaussian distribution for the validity and corrects for all multiple comparisons (i.e. for the collection of test performed for all voxels and for all frequency bands) by employing a locally pooled (smoothed) variance estimate that outperforms the comparable statistical parametric mapping.

Independent t-tests will be used to examine differences between sham and treatment groups for all secondary self-reported outcomes at baseline. Repeated measures analysis of variance (ANOVA) will be conducted with group (sham or treatment) as between subject variable, time as a repeated factor and questionnaire as dependent variable.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/01/2020
Actual
15/02/2020
Date of last participant enrolment
Anticipated
1/11/2021
Actual
1/06/2021
Date of last data collection
Anticipated
1/12/2021
Actual
31/07/2021
Sample size
Target
60
Accrual to date
Final
60
Recruitment outside Australia
Country [1] 21870 0
New Zealand
State/province [1] 21870 0
Otago

Funding & Sponsors
Funding source category [1] 303847 0
University
Name [1] 303847 0
Univiersity of Otago
Country [1] 303847 0
New Zealand
Primary sponsor type
Individual
Name
Tyson Perez
Address
Department of Surgical Sciences
Room 433
Academic Wing
4th floor Dunedin Hospital
210 Great King St
Dunedin, 9016
Country
New Zealand
Secondary sponsor category [1] 303980 0
Individual
Name [1] 303980 0
Prof Dirk De Ridder
Address [1] 303980 0
Section of Neurosurgery,
Department of Surgical Sciences,
Dunedin School of Medicine,
Dunedin Hospital,
201 Great King Street,
Dunedin, 9016
Country [1] 303980 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304360 0
Health and Disability Ethics Committee
Ethics committee address [1] 304360 0
Ethics committee country [1] 304360 0
New Zealand
Date submitted for ethics approval [1] 304360 0
12/09/2019
Approval date [1] 304360 0
15/11/2019
Ethics approval number [1] 304360 0
19/CEN/179

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 96682 0
Prof Dirk De Ridder
Address 96682 0
Section of Neurosurgery,
Department of Surgical Sciences,
Dunedin School of Medicine,
Dunedin Hospital,
201 Great King Street,
Dunedin 9016,
Country 96682 0
New Zealand
Phone 96682 0
+64 3 470 9337
Fax 96682 0
Email 96682 0
dirk.deridder@otago.ac.nz
Contact person for public queries
Name 96683 0
Tyson Perez
Address 96683 0
Department of Surgical Sciences
Room 433, Academic Wing
4th floor Dunedin Hospital
210 Great King St
Dunedin 9016
Country 96683 0
New Zealand
Phone 96683 0
+64 03 474 0999
Fax 96683 0
Email 96683 0
perty770@student.otago.ac.nz
Contact person for scientific queries
Name 96684 0
Tyson Perez
Address 96684 0
Department of Surgical Sciences
Room 433, Academic Wing
4th floor Dunedin Hospital
210 Great King St
Dunedin 9016
Country 96684 0
New Zealand
Phone 96684 0
+64 03 474 0999
Fax 96684 0
Email 96684 0
perty770@student.otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Outcome measure scores
When will data be available (start and end dates)?
01/May/2022 onward and available for 5 years.
Available to whom?
Public
Available for what types of analyses?
To achieve the aims of the clinical study, meta-analyses
How or where can data be obtained?
https://github.com/tysonperez/PhD_rct


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseInfraslow closed-loop brain training for anxiety and depression (ISAD): a protocol for a randomized, double-blind, sham-controlled pilot trial in adult females with internalizing disorders.2022https://dx.doi.org/10.1186/s13063-022-06863-z
N.B. These documents automatically identified may not have been verified by the study sponsor.